Monocyte chemoattractant protein 1 (MCP-1) belongs to the family of chemotactic cytokines known as chemokines. MCP-1 is expressed by a variety of cell types including monocytes, vascular endothelial cells, smooth muscle cells, glomerular mesangial cell, osteoblastic cells, and human pulmonary type-2-like epithelial cells (Sanders, S K. et al. Journal of Immunology, 165: 4877-4883, 2000). It is believed that MCP-1 plays an active role in the initiation and progression of inflammatory diseases, by promoting monocyte influx and subsequent activation in tissues. MCP-1 is chemotactic for monocytes but not neutrophils. It can induce the proliferation and activation of killer cells known as CHAK (CC—chemokine activated killer), which are similar to cells activated by IL-2. It regulates the expression of cell surface antigens (CD11c, CD11b) and the expression of cytokines (IL1, IL6). MCP-1 is a potent activator of human basophils, inducing the degranulation and the release of histamines.
MCP-1 is synthesized in human articular chondrocytes in response to a variety of inflammatory cytokines, and thus may play an active role in the initiation and progression of degenerative and inflammatory arthropathies by promoting monocyte influx and activation in synovial joints. Moreover, elevated levels of MCP-1 are observed in macrophage-rich atherosclerotic plaques. The factor activates the tumoricidal activity of monocytes and macrophages in vivo (www.copewithcytokines.de).
MCP-1 is known to bind and signal through the chemokine receptor, CCR2 (also known as RANTES). CCR2 is a seven trans-membrane-spanning G-protein-coupled receptor expressed on many cells including monocytes, T-cells, B-cells, and basophils. Two MCP-1 specific receptors, CCR2A and CCR2B, have been cloned which signal in response to nanomolar (nM) concentrations of MCP-1
MCP-1 is clearly involved in inflammatory and oxidative stress responses in the vasculature (See Kunsch, C., et al. Circ. 1999 Res. 85: 753-766). MCP-1 appears to play a role in angiogenesis, the formation of new blood vessels. Tumor cell-secreted MCP-1 levels correlate with blood vessel density in a number of tumors, including breast cancer (Saji, H., et al. Cancer, 92: 1085-1091, 2001; Ueno, T., et al. Clin Cancer Res, 6: 3282-3289, 2000), squamous cell carcinoma of head and neck (Liss, C., et al. Int J Cancer, 93: 781-785, 2001) and esophagus (Ohta, M., et al. Int J Cancer, 102: 220-224, 2002), gastric carcinoma (Ohta, M., et al. Int J Oncol, 22: 773-778, 2003), and hemangioma (Isik, F. F., et al. J Surg Res, 61: 71-76, 1996). Furthermore, high levels of tumor MCP-1 were also found to serve as a prognostic biomarker indicating poor prognosis and early relapse (Ueno, et al., 2000 supra; Liss, C., et al. Int J Cancer, 93: 781-785, 2001). It has been postulated that MCP-1 in tumor tissues may stimulate angiogenesis by recruiting tumor infiltrating macrophages and subsequent production of angiogenenic growth factors such as vascular endothelial growth factor, tumor necrosis factor α, and interleukins 6 and 8 (Ueno, T., et al. 2000 supra; Liss, C., et al. 2001, supra). However the precise mechanisms underlying the role of MCP-1 in tumor angiogenesis have yet to be determined.
Other proteins with certain functional and sequence homology to human MCP-1 are known. Especially similar to MCP-1 (GenBank NP—002973) are MCP-2 (GenBank NP—005614) and eotaxin (GenBank P—51671); MCP-2 having 61.8 percent and eotaxin-1 having 63.2 percent sequence identity to MCP-1. The range of activities and spectrum of involvement of these proteins in human homeostatic mechanisms and pathology is not as well understood for the homologs of MCP-1. For example, MCP-2 is related closely to MCP-1 and MCP-3 (Genbank NP—006264) and uses both CCR1 as well as CCR2B as its functional receptors. MCP-3 binds to a receptor designated D6. MCP-3 also binds to CCR10. The MCP-3 protein (97 amino acids) sequence shows 74 percent identity with MCP-1 and 58 percent homology with MCP-2. Secreted MCP-3 differs from MCP-1 in being N-glycosylated. MCP-4 (Genbank NP—005399) shares 56-61 percent sequence identity with the three known monocyte chemotactic proteins and is 60 percent identical with Eotaxin-1. The functions of MCP-4 appear to be highly similar to those of MCP-3 and Eotaxin. Like MCP-3, MCP-4 is a potent chemoattractant for monocytes and T-lymphocytes. It is inactive on neutrophils. On monocytes MCP-4 binds to receptors that recognize MCP-1, MCP-3, and RANTES (CCR2). On eosinophils MCP-4 has similar efficacy and potency as MCP-3, RANTES, and Eotaxin. MCP-4 shares receptors with eotaxin (CCR1 and CCR3) and shows full cross-desensitization with eotaxin-1.
Other antibodies capable of binding MCP-1 have been reported: JP9067399 discloses an antibody obtained from isolated blood cells and JP05276986 discloses a hybridoma secreting an IgM anti-human MCP-1. More recently, antibodies capable of binding a plurality of beta-chemokines including MCP-1 were disclosed (WO03048083) and an MCP-1 binding antibody which also binds eotaxin (US20040047860).
Accordingly, there is a need to provide human antibodies specific for human MCP-1 for use in therapy to diminish or eliminate symptoms of MCP-1-dependent diseases, as well as improvements over known antibodies or fragments thereof.